Oxidized redox state, a new potential biomarker for prostate cancer progression

氧化还原态，前列腺癌进展的新潜在生物标志物

基本信息

批准号：
9039015
负责人：
Luksana Chaiswing
金额：
$ 20.62万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039015
关键词：
4 hydroxynonenal Acceleration Advanced Malignant Neoplasm Affect Antibodies Antioxidants Benign Biochemical Biological Biological Markers Cancer Etiology Cations Cells Cessation of life Characteristics Clinical Couples Cysteine Cystine DNA Sequence Alteration Deoxyguanosine Detection Development Diagnosis Disease Disseminated Malignant Neoplasm Environment Epigenetic Process Epithelial Epithelium Equilibrium Exhibits Freezing Future Gleason Grade for Prostate Cancer Glutathione Glutathione Disulfide Health High Pressure Liquid Chromatography Human Image Image Analysis Imaging technology Immunohistochemistry LNCaP Lead Life Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolic Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Methods Molecular Monitor Mus Mutation Neoplasm Metastasis Nuclear Nude Mice Oxidants Oxidation-Reduction Oxidative Stress PC3 cell line Pathologic Pathologic Processes Pathological Staging Patients Post-Translational Protein Processing Production Property Prostate Proteins Public Health Reactive Nitrogen Species Reactive Oxygen Species Resolution Role Sampling Scanning Sensitivity and Specificity Signal Transduction Site Staging Staining method Stains Sulfhydryl Compounds System TXN gene Techniques Time Tissue Microarray Tissues Transplantation Tumor Suppressor Genes Variant Western Blotting Xenograft procedure base cancer diagnosis clinically relevant comparative extracellular imaging modality improved in vivo interest liquid crystal polymer male men mortality outcome forecast overexpression oxidation oxidative DNA damage oxidative damage potential biomarker prognostic protein expression response sensor specific biomarkers standard of care targeted treatment tempol therapeutic target tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is an increasingly common malignancy worldwide; progression to advanced cancer is highly unpredictable, resulting in a need for new clinically relevant biomarkers or diagnosis tools. A better understanding of PCa pathologic progression would allow development of more sensitive and specific biomarkers. Based on preliminary results from analyses of human PCa tissues, oxidized redox state and posttranslational modification of thioredoxin 1 (Trx1) protein levels were significantly increased in primary PCa with high Gleason scores and metastatic PCa in comparison to adjacent benign tissues. We hypothesize that increased oxidized redox state is contributed to redox imbalance in PCa, leading to increased production of reactive oxygen species/reactive nitrogen species, oxidative DNA damage, mutation of tumor suppressor genes, epigenetic changes, and subsequent PCa progression. To fully understand the relationship of oxidized redox state and PCa progression, a first step involves determining the correlation of oxidized redox state with PCa progression in patient samples. In Specific Aim 1, human PCa-tumor microarrays with different pathological stages will be constructed, stained with oxidative damage products and analyzed using Vectra/Nuance system. Additionally, thiol redox couples will be measured in human prostate frozen tissues with different pathological stages compared to adjacent benign epithelial prostate tissues. Defining the redox state of PCa and its correlation with disease stage is a necessary first step to determine 1) if oxidized redox state may potentially be used as biomarker for PCa diagnosis and 2) whether oxidized redox state is the cause or consequence of PCa progression. Biochemical analyses of redox state in Aim 1 are time-and labor-intensive and require a large amount of tissues. To overcome these problems, Specific Aim 2 will evaluate if TEMPOL-enhanced MRI could potentially be used in the diagnosis of intracellular redox state of prostate cancer in vivo. TEMPOL can undergo oxidation to the corresponding oxoammonium cation by variant oxidants and its paramagnetism property can be captured by MRI. Oxidizing tissues will exhibit longer-lived MRI signal than reducing tissues. We will scan nude mice with orthotopic xenograft transplant LNCaP-luc-M6 or PC3M-luc-C6 cells to evaluate the possibility and validity of TEMPOL-enhanced MRI. To our knowledge, the present proposal will be the first to 1) attempting correlate tissue redox status with the aggressiveness of PCa in patient samples and 2) use cutting edge technique, TEMPOL enhanced MRI to visualize redox state and diagnosis of PCa. Upon completion of these studies, a better understanding of PCa pathologic/metabolic progression may allow development of more sensitive, more relevant, and more specific biomarkers for early prediction or prognosis of those patients destined for clinical cancer progression.

描述（由申请人提供）：前列腺癌（PCa）是世界范围内日益常见的恶性肿瘤；晚期癌症的进展是高度不可预测的，因此需要新的临床相关生物标志物或诊断工具，更好地了解 PCa 病理进展将有助于开发。根据对人类 PCa 组织分析的初步结果，原代细胞中硫氧还蛋白 1 (Trx1) 蛋白的氧化还原状态和翻译后修饰水平显着增加。与邻近良性组织相比，具有高格里森评分的 PCa 和转移性 PCa 我们发现氧化还原状态的增加导致 PCa 中氧化还原失衡，导致活性氧/活性氮的产生增加、氧化 DNA 损伤、肿瘤突变。抑制基因、表观遗传变化和随后的 PCa 进展为了充分了解氧化氧化还原状态与 PCa 进展的关系，第一步涉及确定氧化氧化还原状态与 PCa 进展的相关性。在具体目标 1 中，将构建不同病理阶段的人 PCa 肿瘤微阵列，用氧化损伤产物染色并使用 Vectra/Nuance 系统进行分析。此外，将在不同病理阶段的人前列腺冷冻组织中测量硫醇氧化还原对。与邻近良性上皮前列腺组织相比的病理阶段定义 PCa 的氧化还原状态及其与疾病阶段的相关性。是确定 1) 氧化还原态是否可能用作 PCa 诊断的生物标志物以及 2) 氧化氧化还原态是否是 PCa 进展的原因或结果的必要的第一步，目的 1 中氧化还原态的生化分析是时间和结果。为了克服这些问题，需要大量的劳动力，Specific Aim 2 将评估 TEMPOL 增强 MRI 是否有可能用于诊断前列腺癌的细胞内氧化还原状态。 TEMPOL 可以被不同的氧化剂氧化成相应的氧铵阳离子，并且可以通过 MRI 捕获其顺磁性特性。我们将用原位异种移植 LNCaP-luc 扫描裸鼠。 -M6 或 PC3M-luc-C6 细胞评估 TEMPOL 增强 MRI 的可能性和有效性。目前的提案将是第一个将 1) 尝试将组织氧化还原状态与患者样本中 PCa 的侵袭性联系起来，以及 2) 使用尖端技术、TEMPOL 增强 MRI 来可视化氧化还原状态和 PCa 诊断。了解 PCa 病理/代谢进展可能有助于开发更敏感、更相关和更特异的生物标志物，用于对那些注定要发生临床癌症进展的患者进行早期预测或预后。